This invention relates to therapy for radiation induced tissue damage via antagonism of Transforming Growth Factor .beta. (TGF-.beta.).
Radiation therapy is currently one of the most useful methods of treating cancerous tumors. It has the unfortunate side effect, however, of damaging the normal tissue surrounding the tumor. This damage can include fibrosis, remodeling of the extracellular matrix, vascular damage, aberrant angiogenesis, pneuminitis, atherogenesis, osteonecrosis, mucositis, immunosuppression and functional impairment.
As discovered by the inventor, an early reaction to ionizing radiation is an activation of TGF-.beta., usually within one hour of exposure. (Barcellos-Hoff et al., "Transforming Growth Factor-.beta. Activation in Irradiated Murine Mammary Gland,"J. Clin. Invest., Vol. 93, pp. 892-899, 1994). The first tissue change, a restructuring of the extracellular matrix through collagen III induction, occurs within one day of the radiation exposure. (Barcellos-Hoff, "Radiation-induced Transforming Growth Factor .beta. and Subsequent Extracellular Matrix Reorganization in Murine Mammary Gland," Cancer Research, Vol. 53, pp. 3880-3886, 1993). Fibrosis and other pathologic manifestations of the radiation-induced damage at higher than the cellular level can appear from three weeks to 6 to 12 months post-irradiation. These types of damage are particularly important in the liver, skin, lungs, gastrointestinal tract, kidneys, breast, testes, salivary gland, mucosa and brain.
Because of these radiation-induced side effects on the normal tissue surrounding the cancerous tumor being treated, less radiation can be used than might be optimal in tumor treatment. One researcher has been moved to say, "[w]ere it not for the presence of surrounding normal tissues, the total destruction of tumors by ionizing radiation would be readily achieved." (Murray, "Radiation-induced Fibrosis: the Structure/Function Relationship," Scanning Microscopy, Vol. 8, pp. 79-87, 1994). For example, hepatic veno-occlusive disease is a side effect of radiotherapy combined with bone marrow transplantation for neoplasia affected 15-50 percent of patients. It has a mortality rate of up to 50 percent. (Anscher et al., "Transforming Growth Factor .beta. as a Predictor of Liver and Lung Fibrosis After Autologous Bone Marrow Transplantation for Advanced Breast Cancer," N.E.J.M., 328:1592-1598, 1993).
There are certain patients particularly susceptible to radiation fibrosis because of compromising physical conditions such as systemic sclerosis, collagen vascular disease, systemic lupus erythematosus, and discoid lupus. The radiation treatment of these patients is even more severely limited. Accidental exposure to ionizing radiation in an industrial or research setting can, of course, also lead to fibrosis and the other types of radiation-induced tissue damage.
In order to minimize this radiation-induced damage to surrounding normal tissues, many techniques have been developed in an effort to limit this damage. Most revolve around limiting radiation to the lowest level effective for cancer treatment. Because there is a direct relationship between the amount of radiation and the effectiveness of the treatment, this method compromises the overall effectiveness of the treatment.
Radiation is often administered in as targeted a fashion as possible in an effort to limit damage to normal tissue. However, particularly when treating tissues deep in the body, this approach is not always possible since the radiation must go through layers of normal tissue to reach the cancerous tumor. Implanting a radiation source within the tumor is also used to limit damage to normal tissue. This method results in difficult to monitor dosages, and involves surgical risks. Furthermore, the radiation can still affect surrounding normal tissues.
Some types of fibrosis are currently treated with penicillamine. Use of penicillamine for post hoc treatment of radiation induced fibrosis is experimental. While penicillamine is being tested for anti-fibrosis therapy, the use of this agent does not address other types of radiation induced damage. Even when used in anti-fibrotic therapy, penicillamine has many adverse side effects.
There is a need for a therapeutic method to mitigate radiation induced tissue damage.